This invention relates to a novel class of cephalosporins and analogues thereof and the pharmaceutically acceptable salt, ester, and amide derivatives thereof which bear in the 3-position of the 6-membered ring a substituted thio substituent. These compounds are useful as antibiotics. This invention also relates to processes for preparing such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
The novel class of cephalosporins and analogues thereof to which this invention relates may be generically represented by the following structural formula: ##STR1## wherein THE DOTTED LINE INDICATES PROVISION FOR BOTH .DELTA..sup.2 AND .DELTA..sup.3 EMBODIMENTS;
A is S, O, SO, CH.sub.2, or NR.sup.7, (R.sup.7 is selected from the group consisting of hydrogen, alkyl, formyl, acyl, thioacyl, alkylsulfonyl, and aryl sulfonyl); PA1 R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen or an acyl group. The term acyl is by definition those acyl radicals conventionally known in the cephalosporin and penicillin art and includes thio analogues thereof wherein the carbonyl oxygen is replaced by sulphur and diacyl radicals wherein R.sup.1 and R.sup.2 are joined together. PA1 R.sup.3 is selected from the group consisting of hydrogen, alkoxy, alkylthio, halogen such as fluoro and bromo; PA1 R.sup.5 is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl; aryl, aralkyl, heteroaryl and heteroaralkyl wherein the heterocyclic moiety comprises 4-6 ring atoms and the hetero atom (or atoms) is O, N or S; wherein the ring or chain substituent is selected from: amino, carboxy, hydroxy alkoxy, carbalkoxy, lower alkyl, heteroaryl, and substituted amino such as mono- and di-alkylamino, acylamino; examples of such substituents, R.sup.5 are: .beta.-aminoethyl, .beta.-hydroxyethyl, phenyl, substituted phenyl, benzyl, phenethyl and the like; and PA1 R.sup.6 is selected from the group consisting of PO(OH).sub.2, SO.sub.2 (OH), SO.sub.2 NH.sub.2 and derivatives thereof and COXR.sup.8 wherein X is oxygen or sulphur and R.sup.8, is inter alia, representatively selected from the group consisting of trialkylsilyl, and the pharmaceutically acceptable salt, ester and amide moieties known in the antibiotic bicyclic .beta.-lactam art such as sodium, potassium, pivaloyloxymethyl, and the like. PA1 A is selected from S, CH.sub.2, SO, and O; PA1 R.sup.3 is selected from hydrogen, methoxyl, and lower alkyl thio. PA1 R.sup.5 is hydrogen formyl or --(CH.sub.2).sub.n --Y wherein Y is hydrogen, hydroxyl, halo, mercapto, acyloxy, acylthio, substituted hydroxy, substituted mercapto, a quaternary ammonium group, azido, amino, carboxy and carbalkoxy, or an N-substituted amino group; and PA1 n is an integer from 1 to 6 and preferably 1 to 3. PA1 R.sup.1, r.sup.2 and R.sup.6 are as previously defined; PA1 R.sup.3 is selected from the group consisting of H, OCH.sub.3 and lower alkylthio having from 1 to 6 carbon atoms; PA1 R.sup.5 is selected from the group consisting of hydrogen, lower alkyl having 1 to 6 carbon atoms, substituted phenyl, N-methyltetrazolyl, amino alkyl such as .beta.-aminoethyl, .beta.-dimethylaminoethyl, .beta.-thioethyl, .beta.-hydroxyethyl, .beta.-carboxyethyl, and 2-methyl-1,3,4-thiadiazolyl-5yl.
There is a continuing need for new antibiotics. For, unfortunately, there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to strains of pathogens which are resistant to the exploited antibiotic. In addition, the known antibiotics suffer from the disadvantage that they are effective only against certain types of microorganisms. Accordingly, the search for new antibiotics has continued.
Unexpectedly, it has been discovered that the compounds of the present invention are broad spectrum antibiotics; which are useful in animal and human therapy and in inanimate systems. It will be recognized from the above generic representation (I) that the principal novel feature of the compounds of the present invention is the substituent at the 3-position, a substituted thio radical. It will also be noted, except where expressly stated, that the balance of the cephalosporin or cephalosporin-like structure (I) is well-known in the relevant art.
Thus, it is an object of the present invention to provide a novel class of antibiotics which includes, inter alia, species having the basic nuclear structure of the cephalosporins but which are characterized by having a substituted thio radical at the three-position. These antibiotics are active against a broad range of pathogens, which representatively include gram positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and gram negative bacteria such as E. coli and Salmonella typhimurium, Proteus mirabilis, and Proteus morganii. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics; intermediates useful in preparing such antibiotics; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.